Natural products have provided a wide range of biologically active agents many of which have unique profiles of pharmacological activity and therapeutic potential. Over two hundred alkaloids have been identified in extracts from amphibian skins. These include batrachotoxins, which are potent activators of sodium channels, histrionicotoxins, which are noncompetitive blocks of nicotinic receptor channel complexes and of potassium channels and pumiliotoxins, which have myotonic and cardiotonic activity due to inhibitory effects on closing of sodium channels. The effects of pumiliotoxin B on sodium channels results in repetitive activations of such channels, enhancement of neurotransmitter release, and potentiation of contraction is striated and cardiac muscle. The stimulatory effects of pumiliotoxins, pyrethroids and other sodium channel agents on cardiac function correlates with stimulation of phosphoinositide turnover leading to both mobilization of internal calcium and to activation of protein kinase C. The effects of pumiliotoxin B on sodium flux in synaptoneurosomes are markedly potentiation by certain polypeptide toxins, such as alpha-scorpion toxin. A variety of 2,6- disubstituted piperidines are potent noncompetitive blockers of the nicotinic receptor-channel complex. Those with one long side chain stabilize high affinity desensitized states of the receptor. Local anesthetics inhibit binding of a tritiated batrochotoxin analog either allosterically by enhancing dissociation or through direct competition. Reserpines appear to be true competitors. New structural classes of amphibian alkaloids have been delineated and include 2,5-disubstituted pyrrolidines, a 4-hydroxy- 2, 6-dialkylpiperidine, 2,5-disubstituted-trans- decahydroquinolines, a quinolizidine related in structure to the pumiliotoxin-A class of alkaloids, various 5-substituted-8-methyl indolizidines a hydroxypumiliotoxin C, an azatricyclododecene, several tricyclic amidines, and an unusual prenyl pyrrole-(2,3-b) indole ester. The biological activity of these new alkaloids is unknown.